Polycystic kidney disease (PKD) is the most common inherited cause of end-stage renal disease afflicting an estimated 1 in 500 to 1 in 1000 persons. The two most prominent, inherited forms of PKD are autosomal dominant (ADPKD) generally characterized as being asymptomatic until adulthood, while autosomal recessive (ARPKD) is usually symptomatic in the perinatal or infantile period. The genes for ADPKD (i.e., ADPKD1 or polycystin, and ADPKD2) have been cloned and sequenced. The functional role of these unique and very different proteins in initiating cysts is not known. The chromosomal locations for the ARPKD gene in humans and the mouse model (the C57BL/6J-cpk/cpk mouse) have been identified but neither gene has been cloned.
Renal cysts are among the most common pathological structures observed in kidneys. Mangoo-Karim et al., Proc. Natl. Acad. Sci. USA, 86: 6007-11 (1989)..sup.1 Cysts derive from nephron and collecting duct tissue and are isolated collections of urine-like fluid surrounded by a continuous epithelial layer. Cysts may be solitary and relatively innocent or so numerous (i.e., polycystic) that they compress and distort normal parenchyma and thereby cause renal insufficiency. Mangoo-Karim et al., supra. FNT .sup.1 All literature referred to herein is hereby incorporated by reference.
Renal cyst formation and enlargement is the product of a highly coordinated integration among three central processes: epithelial proliferation, fluid accumulation within the cyst cavity, and remodeling of the interstitium (matrix) that surrounds the cysts. Mangoo-Karim et al., supra. See also Cowley et al., Proc. Natl. Acad. Sci. USA, 84: 8394-98 (1987); Grantham et al., Kidney Int., 31: 1145-52 (1987); Carone et al., Am. J. Pathol., 130: 466-71 (1988); and Grantham et al., Kidney Int., 35: 1379-89 (1989).
The development of PKD has two distinct phases--the initiation of cysts and cyst progression. The collecting duct is the major tubule affected by the cystic change in ARPKD, and is largely responsible for concentrating urine. Although the defective genes probably control the initiation of cysts, there are a number of factors which appear to contribute to the progression of PKD. Polyuria with a renal concentrating defect is found in virtually all forms of inherited PKD and may contribute to the progression of the cystic disease. The basis for this defect is not understood.
Urine concentration in the collecting ducts requires three conditions: (1) A hypertonic interstitium to serve as the osmotic gradient for directional water movement; (2) arginine vasopressin (AVP) and its collecting duct cell receptor (the AVP-V.sub.2 receptor); and (3) stimulation of the water channels aquaporin-2 (AQP2) and aquaporin-3 (AQP3) by AVP such that AQP2 is inserted into the apical membrane while AQP3 is localized to the basolateral membrane. PKD produces a condition which appears similar in many respects to nephrogenic diabetes insipidus (DI). Inherited nephrogenic DI is usually caused by a defect in either the AVP-V.sub.2 receptor or AQP2 genes, neither of which are affected by the ADPKD mutations. While preliminary data from Yamaji et al. (1995) indicate that ADPKD kidneys have AQP2, AVP stimulation of ADPKD cysts does not stimulate AQP2 insertion into the apical membrane. These data indicate an interesting and unique functional deficit in PKD. It is unclear why or when this collecting duct abnormality develops.
Gabow et al. (1989) described the concentrating defect as an early event which can be used for the identification of affected individuals within an ADPKD family. A number of researchers have looked at structural distortion, AVP, urinary concentrating ability, renal insufficiency and the renin-angiotensin system in hypertensive and normotensive ADPKD patients to determine relationships critical to the development of hypertension and progression to renal failure. The renal concentrating defect correlates positively with renal insufficiency and structural distortion of the kidney (Gabow et al., 1989). A role for atrial natriuretic peptide (ANP) (Sorenson et al., 1990), medullary architecture (Anand et al., 1975; Gabow et al., 1989), and an increase in aquaporin-1 (CHIP-28) (Bachinsky et al., 1995) are hypothesized to play a role. However, the basis for the concentrating defect remains elusive. Early studies described the renal concentrating defect as unresponsive to AVP (Martinez-Maldonado et al., 1972). It has been reported that AVP levels are elevated in hypertensive individuals with ADPKD (Danielson et al., 1986a), and all ADPKD patients after volume expansion with hypertonic saline, as compared to control (Danielson et al., 1986b). Therefore, the ligand appears to be present in elevated concentrations in those with ADPKD.
Data indicate that AVP binding to a small fraction of the receptors is sufficient to initiate a maximal response (Abramow et al., 1987) suggesting that ligand is generally the limiting factor. However, cultured ADPKD cells exhibited an attenuated response to AVP (Wilson et al., 1986) suggesting an inherent defect in the vasopressin receptor system as well.
This could be due to the abnormal response of cystic epithelial cells to AVP as described by Yamaji et al. (1995). Prior to Applicant's research described below, there was no literature on the expression AVP receptors in PKD.
Evidence from in vitro studies suggests that increased proliferation of epithelial cells and secretion of fluid by these cells may be important factors in the progressive enlargement of renal cysts. The rate of enlargement in vitro can be accelerated by cyclic adenosine 3'5' monophosphate (cAMP) and agonists that lead to the production of cAMP. See Mangoo-Karim et al., supra.
Research has been conducted examining the role of the cystic fibrosis transmembrane conductance regulator (CFTR) and the lipid cyst activating factor (CAF) in PKD. See, e.g., Davidow et al., Kidney Int. 50(1): 208-218 (1996); Yamaguchi et al., Am. J. Kidney Dis., 30(5): 703-709 (November 1997). Both CFTR and CAF are mediated by cAMP, and thus far CAF has been implicated in increasing renal cAMP. Yamaguchi et al., supra. Activation of the vasopressin V.sub.2 receptor is also mediated by G-proteins (guanyl nucleotide regulatory proteins) and cAMP. Carmichael et al., Sem. in Nephrology, 14(4): 341-48 (1994). However, more than 240 G-protein-coupled receptors have been cloned and those mediated by cAMP are abundant not only in the kidney but throughout the body. For example, cAMP may be abnormally increased by parathyroid hormone or prostaglandins. Thus, identifying the source(s) of increased cAMP and treating this imbalance has proved to be problematic.
Currently, there is no treatment for PKD other than agents to manage the sequelae of the disease. For example, angiotensin II inhibitors like captopril are often used to control the associated hypertension which is allegedly partially mediated by renin. Therefore, a definite need exists for therapies directed at the progression mechanisms of the disease.